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27 Jun 2018 - 29 Jun 2018
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Mycobacteria Use Voltage-Dependent Channels to Prevent Destruction

By BiotechDaily International staff writers
Posted on 14 Sep 2017
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Image: A photomicrograph of the pathogenic bacterium Mycobacterium avium (Photo courtesy of Wikimedia Commons).
Image: A photomicrograph of the pathogenic bacterium Mycobacterium avium (Photo courtesy of Wikimedia Commons).
A team of molecular microbiologists unraveled the mechanism whereby the pathogenic bacterium Mycobacterium avium modifies the environment inside the macrophage phagosome and transforms it from a killing site to place for growth and reproduction.

M. avium is associated with infection of immunocompromised individuals as well as patients with chronic lung disease. This pathogen infects macrophages and actively interferes with the host killing machinery such as apoptosis and autophagy. The bacteria alter the normal endosomal trafficking, prevent the maturation of phagosomes and modify many signaling pathways inside of the macrophage by secreting effector molecules into the cytoplasm.

Phagosomes are vesicles formed around particles engulfed by phagocytes such as macrophages, neutrophils, and dendritic cells. A phagosome is formed by the fusion of the cell membrane around the microorganism. Phagosomes have membrane-bound proteins to recruit and fuse with lysosomes to form mature phagolysosomes. The lysosomes contain hydrolytic enzymes and reactive oxygen species (ROS), which kill and digest the pathogens Many Mycobacteria, including Mycobacterium tuberculosis and Mycobacterium avium, can manipulate the host macrophage to prevent lysosomes from fusing with phagosomes and creating mature phagolysosomes. Such incomplete maturation of the phagosome maintains an environment favorable to the pathogens inside it.

To identify possible phagosomal proteins that were employed by M. avium to export virulence factors into the cytosol of host cells, investigators at Oregon State University (Corvallis, USA) purified vacuole membrane proteins, and their binding to the surface molecules present in intracellular bacteria was evaluated.

The investigators reported in the August 1, 2017, online edition of the journal Scientific Reports that they had identified voltage-dependent anion channels (VDAC) as components of M. avium vacuoles in macrophages. M. avium mmpL4 proteins were found to bind to VDAC-1 protein. The inactivation of VDAC-1 function either by pharmacological means or siRNA (short inhibiting RNA) led to significant decrease of M. avium survival. Although, they could not establish a role of VDAC channels in the transport of known secreted M. avium proteins, the investigators demonstrated that the porin channels were associated with the export of bacterial cell wall lipids outside of vacuole.

"The idea is to find out the mechanism bacteria use to secrete proteins produced in the cells that have important functions in controlling the phagocytic activity that is supposed to kill them," said senior author Dr. Luiz Bermudez, professor of veterinary medicine at Oregon State University. "A VDAC is very small, but it can become larger if several VDAC proteins get together through polymerization. We found that yes, mycobacteria use surface proteins to bind to the VDAC. But although we tried to see if the proteins of the mycobacterium were exported by the VDAC, we could not show that. However, we did show that another component of the cell wall of the mycobacterium, lipids, are exported by that mechanism."

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